Hypercholesterolemia is known to be one of the prime risk factors for ischemic cardiovascular disease, such as arteriosclerosis. Bile acid sequestrants have been used to treat this condition; they seem to be moderately effective but they must be consumed in large quantities, i.e. several grams at a time and they are not very palatable.
Mevacor.RTM. (lovastatin), now commercially available, is one of a group of very active antihypercholesterolemic agents that function by limiting cholesterol biosynthesis by inhibiting the enzyme, HMG-CoA reductase. In addition to the natural fermentation products, mevastatin and lovastatin, there are a variety of semi-synthetic and totally synthetic analogs thereof.
The naturally occurring compounds and their semi-synthetic analogs have the following general structural formulae: ##STR1## wherein: Z* is hydrogen, C.sub.1-5 alkyl or C.sub.1-5 alkyl substituted with a member of the group consisting of phenyl, dimethylamino, or acetylamino; and
R* is: ##STR2## wherein Q is ##STR3## R.sup.3 is H or OH; and R.sup.2 is hydrogen or methyl; and a, b, c, and d represent optional double bonds, especially where b and d represent double bonds or a, b, c, and d are all single bonds, provided that when a is a double bond, Q is ##STR4## PA1 R.sub.1 is CH.sub.3, CH.sub.2 OH, ##STR7## CO.sub.2 R.sub.3 ##STR8## OH, CH.sub.2 OR.sub.2 or CH.sub.2 NR.sub.4 R.sub.5 ; R.sub.2 is C.sub.1-5 alkyl; PA1 R.sub.3 is H or C.sub.1-5 alkyl; PA1 R.sub.4 and R.sub.5 are independently selected from H or C.sub.1-10 alkyl; PA1 R.sub.1 is CH.sub.3, CH.sub.2 OH, ##STR10## CO.sub.2 R.sub.3, ##STR11## OH, CH.sub.2 OR.sub.2, or CH.sub.2 NR.sub.4 R.sub.5 ; Z is H or NH.sub.4 + or a metal cation; PA1 R.sub.2 is C.sub.1-5 alkyl; PA1 R.sub.3 is H or C.sub.1-5 alkyl; PA1 R.sub.4 and R.sub.5 are independently selected from H or C.sub.1-5 alkyl; a and b are both double bonds or one of a and b is a single bond or both a and b are single bonds. PA1 R is C.sub.1-10 alkyl, PA1 R.sub.1 is CH.sub.3 ; and PA1 Z is H+ or NH.sub.4 +.
The preparation of the naturally occurring compounds and their semi-synthetic analogs leads to a mixture of the lactone and dihydroxy acid forms. Mevacor.RTM. is marketed in the lactone form and thus it is of considerable importance to employ a high yield efficient method for the lactonization of the free acid or salt form. In the past, lactonization of the free acid or ammonium salt was effected by heating these substrates in a neutral organic solvent such as toluene, ethyl acetate, or isopropyl acetate at or near reflux. The lactonization is catalyzed by the presence of acid. The necessary acidity arises either through the ambient acidity of the substrate itself or by the addition of a stonger acid to effect lactonization at a lower temperature.
Lactonization is an equilibrium process, and in order to obtain a high yield of the lactone product, some means must be employed to shift the equilibrium to the lactone side of the equation: EQU Dihydroxy acid (or NH.sub.4.sup.+ salt).revreaction.Lactone+H.sub.2 O(+NH.sub.3)
In the prior procedures, lactonization is forced to near completion by removing the reaction by-products (water, ammonia) from the reaction mixture by means of azeotropic distillation and/or nitrogen sweep. The removal of water, and in the case of the ammonium salt ammonia, shifts the position of equilibrium to the lactone side.
Prior lactonization procedures exhibited several disadvantages. Typically the hydroxy acid substrate acted as the acid catalyst and thus as the substrate was consumed, the rate of reaction decreased requiring longer reaction times and allowing for increased by-product formation. Under the reaction conditions, the product 3-hydroxylactone is exposed for prolonged periods of time to the free acid which leads to increased amounts of a dimer (1) which results from an esterification reaction between the 3-hydroxyl group of the 3-hydroxylactone and the free acid. ##STR5##
The above dimer impurity has proved to be difficult to separate from the desired lactone product even with careful recrystallization techniques. The presence of the dimer, of course, lowers the overall yield and purity of the lactone product. Efforts to minimize the formation of the dimer have led to the use of high dilution in the lactonization reaction, however, this technique compromises the efficiency of the reaction.
A second impurity, resulting from dehydration of the 3-hydroxyl group on the lactone ring, was also observed using prior lactonization conditions. This impurity was likewise only inefficiently removed by recrystallization, resulting in diminished yields. The present invention alleviates this problem.